Iniparib, 4-iodo-3-nitrobenzamide (Formula 1), is undergoing clinical trials for the treatment of certain types of breast cancer.

Its action is attributed to inhibition of poly-ADP-ribose-polymerase (PARP).
Its preparation is described in U.S. Pat. Nos. 5,464,871 and 5,877,185. The method described in the '871 and '185 patents, involves reacting 4-iodo-3-nitrobenzoic acid with thionyl chloride in dimethylformamide (DMF) to obtain the acid chloride in situ, followed by reaction with ammonium hydroxide (Scheme-1), with about 48.8% crude yield. After recrystallization from acetonitrile solvent, a yield of only 40.5% was obtained. The recrystallized product showed signals for acetonitrile in 1H-NMR. The integration of the acetonitrile signal indicates approximately one molecule of acetonitrile per three molecules of 4-iodo-3-nitrobenzamide.
This was further confirmed by elemental analysis data. Acetonitrile is not a safe chemical since it metabolizes to give highly toxic hydrogen cyanide.

Another major problem encountered while preparing 4-iodo-3-nitrobenzamide using the above method is the formation of 4-chloro-3-nitrobenzamide as an impurity. During the reaction with thionyl chloride, a nucleophilic aromatic substitution of 4-iodo with chloro to give 4-chloro-3-nitrobenzamide was observed (Scheme 2) as a side reaction.

The iodo group is activated for such a nucleophilic substitution because of the presence of a nitro group at the ortho position in the benzene ring. Further, the reaction is facilitated by the use of DMF, an aprotic solvent. The authors observed about 2-5% of the chloro impurity (U.S. '871 and '185). Even after repeated crystallizations, the impurity could not be removed completely but resulted in significant loss in yield of the required compound.
Thus, the synthetic process described in the prior art suffers from:                1. low yields;        2. presence of residual acetonitrile in the final product; and        3. formation of 4-chloro-3-nitrobenzamide as an impurity.        